N-substituted (.alpha.-amino acids (such as in formula I) and dipeptides (such as in formula II) containing them are valuable intermediate products for the production of inhibitors of the angiotensin converting enzyme (ACE) which are highly interesting as regulators of blood pressure. A few such N-substituted dimeprides are already commercially available as medicines or are in the registration stage, e.g. enalapril (N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-L-proline), lisinopril (N-[(S) -1-carboxy-3-phenylpropyl]-L-lysyl-L-proline) or ramipril (2-[N-[(S)-1-ethoxycarbonyl-3-phenyl-propyl]-L-alanyl]-(1S, 3S, 5S)-2-azabicyclo[3,3,0]-octane-3-carboxylic acid).
Such a method is described in J. Org. Chem. 1988, 53, pp. 836-844 for the production of compounds of formula II. Absolute ethanol serves as inert solvent, a molecular sieve for the removal of water and Raney nickel as hydrogenation catalyst. The products produced thereby are obtained in a 42-80 % yield according to the literature. However, these yields can be difficult to reproduce and, in addition, considerable amounts of byproducts usually remain in the products. This makes it difficult to purify them to pharmaceutically useful products.
A reductive amination of an amino acid ester with pyruvic acid is described in J. Med. Chem 28 (1985), pp. 1596-1602. The amino acid ester is used as hydrochloride. A small amount of NaOH is dissolved in the solvent, which liberates the amine from the amino acid ester hydrochloride and for the partial neutralization of the pyruvic acid. On the whole, there is an excess of acid in the reaction mixture, because of the pyruvic acid.
U.S. Pat. No. 4,474,692, especially examples 2, 7-14 and 21, teaches reductive aminations of dipeptides with .alpha.-keto acids. A buffer of sodium acetate and acetic acid is contained in the reaction mixture. The acetic acid is present the buffer in approximately double the molar excess.